Fermentation capacity of the gut microbiota influences exercise motivation and neuroendocrine integration.

Physical inactivity contributes substantially to global disease burden, yet the physiological mechanisms underlying exercise motivation remain poorly understood. The gut-brain axis presents a potentially modifiable target for behavioral intervention. Emerging evidence demonstrates that the gut microbiota influences motivated behaviors, but the specific metabolic functions and physiological mechanisms mediating these effects remain poorly defined. Here, we demonstrate that the predicted fermentation capacity of the gut microbiota influences voluntary wheel running (VWR) acquisition and neuroendocrine integration during exercise in C57BL/6J mice. Antibiotic-induced microbiome depletion reduced VWR acquisition, while shifting predicted function toward aerobic respiration and away from anaerobic fermentation. Supplementation with short-chain fatty acids, the primary fermentative products, restored normal VWR activity in microbiome-depleted mice. Conversely, 4-week dietary pretreatment with 2.5% prebiotic fiber (inulin) increased predicted fermentative capacity of the microbiota and VWR activity above baseline levels. Microbiome manipulation produced bidirectional dysregulation of corticosterone responses to exercise: acute antibiotic depletion increased post-exercise concentrations, while germ-free development decreased them, despite elevated striatal catecholamines. This exercise-specific uncoupling reveals microbiome-dependent integration of metabolic demand signals in the coordination of sympathetic and hypothalamic-pituitary-adrenal axis responses. Furthermore, the inulin-induced enhancement in VWR activity was associated with increased striatal histamine concentrations following exercise, suggesting additional mechanisms of neuromodulation. These findings demonstrate that the fermentative capacity of the gut microbiota influences exercise motivation and neuroendocrine regulation, providing novel insights into dietary interventions targeting physical activity. IMPORTANCE: Physical inactivity is a leading cause of global morbidity and mortality, and our lack of understanding of the biological forces driving motivation to exercise limits our ability to develop interventions that enhance engagement. Using a rodent model of voluntary exercise along with microbiota depletion and metabolite replacement, we uncovered that the gut microbiota and its capacity to ferment dietary components into short-chain fatty acids drive exercise habit acquisition and help facilitate coordination between neurochemical signals and systemic stress hormones during exercise. Additionally, microbiome depletion "uncoupled" these systems, resulting in dysregulated stress responses during forced exercise. Finally, we showed that enhancement of microbiota fermentation capacity via dietary addition of prebiotic fiber was able to increase exercise engagement while also enhancing concentrations of histamine, a neuromodulator that potentiates locomotor activity, in the striatum. These findings suggest that the gut microbiome is a modifiable target for behavior change that facilitates integration of metabolic demand in neuroendocrine activity. Collectively, this work provides a mechanistic foundation to support the use of dietary interventions in sedentary populations to start exercise habits.